The sequence and mechanism of the vascular response to ischemia will be investigated using the arterially perfused rabbit interventricular septum. The ischemic response will be described in terms of changes in 1) capillary permeability as determined through 131I-albumin labelling, 2) extracellular space measured with 58Co-EDTA labelling, 3) true vascular space estimated with 51Cr-RBC's, 4) arteriovenous shunting determined by microsphere infusion, 5) perfusion pressure (and thus vascular resistance), and 6), total tissue H2O; these parameters will be correlated with muscle contractile function and vascular ultrastructural appearance. A hypothesis is advanced that the initiating factor in ischemic vascular injury is an increase in vascular resistance secondary to increased Ca influx and/or decreased internal Ca sequestration in vascular smooth muscle. This will be tested by comparing the effects of manipulations which 1) retard Ca influx (verapamil, low perfusate Ca concentration), 2) influence internal Ca effects on vascular contraction (adenosine, nitroprusside), or 3) exert non-specific vasodilating effects (mannitol). These manipulations will be tested after varying periods of ischemia with regard to their effects on the previously mentioned parameters, permitting the temporal correlation of vascular exchange characteristics, permeability, flow and muscle recovery after ischemia.